Sleep deprivation elevates, and sleep alleviates, oxidative stress in the brain.

摘要 由于尚不清楚的原因，睡眠对于扭转认知和表现的缺陷至关重要 在长时间的觉醒过程中会随着严重程度的增加而积累。最健壮、最可靠的 睡眠的特征是大脑新陈代谢的降低，表现为大脑温度的下降和 脑部葡萄糖和氧气利用率下降，与觉醒相关。顺理成章的是，新陈代谢下降 状态对于睡眠的恢复功能是必不可少的，但这种关系的生化基础是 不确定。葡萄糖的氧化代谢促进了神经元的活动。验尸结果表明 长时间的觉醒会导致大脑中氧化应激的积累。我们假设减少了 睡眠中的葡萄糖利用逆转了代谢驱动的氧化还原状态的转变(平衡 高代谢所致的小白蛋白阳性神经元的氧化还原反应 清醒的大脑对这些细胞的需求。我们进一步假设睡眠的这个功能是 部分是由一种称为神经周围神经网络的细胞外基质结构促进的，它起到了 在代谢脆弱的神经元中缓冲氧化应激。为了解决这些假设，我们 将执行系统的药物操作(氧化/还原反应底物烟碱 腺嘌呤二核苷酸)会影响大脑抵抗氧化应激的能力。我们还将评估 进行脑区特定区域神经周围神经网络的耗竭。我们将评估这些措施的影响 操作，以及睡眠/觉醒周期操作，在细胞氧化还原状态标记物上，两者都是真实的- 活体显微镜下的活体时间，以及结合氧化分析和细胞类型特异性的死后时间 神经周围神经网络强度的免疫化学标记和组织化学评价。我们还会另外 测量实验操作对脑疲劳脑电标志物的影响 和睡眠需求。预期的结果将建立睡眠/清醒周期之间的因果关系 和大脑氧化还原状态，并将确定大脑氧化/还原反应作为这两个诊断的目标 面对睡眠不足的询问和治疗干预。 1

Abstract For reasons that remain unknown, sleep is essential for the reversal of deficits in cognition and performance that accumulate with increased severity during protracted wake. One of the most robust and reliable features of sleep is a reduction of cerebral metabolism, manifested by a decline in brain temperature and a decline in brain glucose and oxygen utilization, relative to wake. It stands to reason that the metabolic down state is essential for the restorative function of sleep, yet the biochemical basis for this relationship is uncertain. Oxidative metabolism of glucose fuels neuronal activity. Postmortem assays indicate that protracted wake produces an accumulation of oxidative stress in the brain. We hypothesize that reduced glucose utilization in sleep reverses a metabolically-driven shift in the redox status (the balance of oxidation and reduction reactions) of parvalbumin-positive neurons caused by the high metabolic demand of these cells in the waking brain. We further hypothesize that this function of sleep is facilitated in part by an extracellular matrix structure known as perineuronal nets, which serve to buffer against oxidative stress in metabolically vulnerable neurons. To address these hypotheses, we will perform a systemic pharmacological manipulations (the oxidation/reduction reaction substrate nicotinic adenine dinucleotide) known to affect the brain’s capacity to withstand oxidative stress. We will also assess perform brain region-specific depletion of perineuronal nets. We will assess the effects of these manipulations, and those of sleep/wake cycle manipulations, on cellular redox status markers, both in real- time in vivo using intravital microscopy, and post mortem by coupling oxidation assays with cell type-specific immunochemical markers and histochemical assessment of perineuronal net intensity. We will additionally measure the effects of the experimental manipulations on electroencephalographic markers for brain fatigue and sleep need. The anticipated results will establish a causal interrelationship between sleep/wake cycles and brain redox status, and will identify brain oxidation/reduction reactions as a target for both diagnostic inquiry and therapeutic intervention in the face of sleep insufficiency. 1